Lymphoma Tumor Biology

Lymphoma Tumor Biology

MUDr. Ondřej Havránek, Ph.D.

MUDr. Ondřej Havránek, Ph.D. — Project head

About us

Non-Hodgkin lymphomas are a heterogenous group of hematologic malignancies derived in more than 90% from B-lymphocytes, one subtype of white blood cells. B-cells are part of adaptive immune system and one of their main functions is to recognize antigens and differentiate into plasmatic cells to produce antibodies. Hallmark molecule of B-cells is B-cell receptor (BCR), which is specifically responsible for antigen binding and recognition. Majority of B-cell derived malignancies retain surface expression of BCR, which is actively signaling and supports growth and survival of tumor cells.

Similarly, as is heterogonous group of lymphomas, differences exist also in types of signaling it provides. In some lymphomas, BCR signals through “chronic active” type of BCR signaling that resembles normal signaling after antigen binding, in other lymphomas, BCR signaling resembles “tonic” type of signaling that normally provides basic signal necessary for survival of mature B-cells. However, many details and differences in BCR signal initiation and its transmission to individual signal mediators are not fully characterized. Inhibition of BCR signaling and its related signal mediators is also one of novel strategies of lymphoma treatment, but more information is needed to identify novel therapeutic targets or personalize use of existing inhibitors.

Latest developments in technology and related research resulted in unprecedented advancement in our understanding of mechanisms leading to lymphomagenesis, however, many mechanisms of aberrant signaling, metabolic changes, transcription regulation, or interactions of tumor cells with tumor microenvironment are still not clear.

Using advanced methods for targeted genomic modifications, protein-protein interactions detection, high-resolution microscopy, or intracellular biosensors, the general aim of our group is to address missing information about cellular processes critical for lymphoma development and tumor cell growth with contribution to basic knowledge of these processes in general.

 Specific Projects:

  • Describe differences and mechanisms of B-cell receptor signal initiation, its localization and interaction with signal mediators, and mechanisms of PI3K/AKT pathway activation in different types lymphomas and states of BCR signaling.
  • Identify biomarkers to personalize use of BCR signaling inhibitors.
  • Investigate novel candidates for gene expression dysregulation in lymphoma.
  • Investigate relationship of driver lymphoma characteristics on development of tumor microenvironment using lymphoma mouse models.

Further information can be found also at https://havranek-lab.lf1.cuni.cz/about-us

News

Publications

2020

Jain N, Singh S, Laliotis G, Hart A, Muhowski E, Kupcova K, Chrbolkova T, Khashab T, Chowdhury SM, Sircar A, Shirazi F, Singh RK, Alinari L, Zhu J, Havranek O, Tsichlis P, Woyach J, Baiocchi R, Samaniego F, Sehgal L. Targeting phosphatidylinositol 3 kinase-β and -δ for Bruton tyrosine kinase resistance in diffuse large B-cell lymphoma. Blood Adv 2020 Sep 22;4(18):4382-4392. (2019 IF 4.6)

Vockova P, Molinsky J, Klanova M, Karban J, Spacek M, Havranek O, Kupcova K, Kazantsev D, Trneny M, Klener P. CD31/PECAM-1 impacts engraftment, growth and spread of mantle cell lymphoma cells and positively correlates with extramedullary involvement. Leuk Lymphoma. 2020 Nov 25:1-8. doi: 10.1080/10428194.2020.1849678. (IF 2.969)

2019

Prukova D, Andera L, Nahacka Z, Karolova J, Svaton M, Klanova M, Havranek O, Soukup J, Svobodova K, Zemanova Z, Tuskova D, Pokorna E, Helman K, Forsterova K, Pacheco-Blanco M, Vockova P, Berkova A, Fronkova E, Trneny M, Klener P. Co-targeting of BCL2 with venetoclax and MCL1 with S63845 is synthetically lethal in vivo in relapsed mantle cell lymphoma. Clin Cancer Res. 2019 Jul 15;25(14):4455-4465. (2019 IF 10.1)

Jain N, Harter K, Tadros S, Fiskus W, Havranek O, Ma MCJ, Bouska A, Heavican T, Kumar D, Deng Q, Moore D, Pak C, Liu CL, Gentles AJ, Hartmann E, Kridel R, Smedby E, Juliusson G, Rosenquist R, Gascoyne RD, Rosenwald A, Giancotti F, Neelapu SS, Westin J, Vose JM, Lunning MA, Greiner T, Rodig S, Iqbal J, Alizadeh AA, Davis RE, Bhalla K, Green MR. Targetable genetic alterations of TCF4 (E2-2) drive immunoglobulin expression in diffuse large B-cell lymphoma. Science Translational Medicine 2019 Jun 19;11(497) (2019 IF 16.3)

Kleiblova P, Stolarova L, Krizova K, Lhota F, Hojny J, Zemankova P, Havranek O, Vocka M, Cerna M, Lhotova K, Borecka M, Janatova M, Soukupova J, Stribrna J, Sevcik J, Zimovjanova M, Kotlas J, Panczak A, Vesela K, Zidovska J, Cervenkova J, Schneiderova M, Burocziova M, Burdova K, Stranecky V, Foretova L, Machackova E, Tavandzis S, Kmoch S, Macurek L, Kleibl Z. Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer. Int J Cancer. 2019 Oct 1;145(7):1782-1797 (2019 IF=5.1)

2017

Havranek O, Xu J, Köhrer S, Wang Z, Becker L, Comer JM, Henderson J, Ma W, Man Chun Ma J, Westin JR, Ghosh D, Shinners N, Sun L, Yi AF, Karri AR, Burger JA, Zal T, Davis RE. Tonic B-cell receptor signaling in diffuse large B-cell lymphoma. Blood. 2017 Aug 24;130(8):995-1006. (2017 IF 15.3)

Mathur R, Sehgal L, Havranek O, Kohrer S, Khashab T, Jain N, Burger JA, Neelapu SS, Davis RE, Samaniego F. Inhibition of demethylase KDM6B sensitizes diffuse large B-cell lymphoma to chemotherapeutic drugs. Haematologica. 2017 Feb;102(2):373-380 (2017 IF 9.1)

Vangapandu HV, Havranek O, Ayres ML, Kaipparettu BA, Balakrishnan K, Wierda WG, Keating MJ, Davis RE, Stellrecht CM, Gandhi V. B-cell Receptor Signaling Regulates Metabolism in Chronic Lymphocytic Leukemia. Mol Cancer Res. 2017 Dec;15(12):1692-1703. (2017 IF 4.6)

2016

Koehrer S, Havranek O, Seyfried F, Hurtz C, Coffey GP, Kim E, Hacken E, Jäger U, Vanura K, O’Brien S, Thomas DA, Kantarjian H, Ghosh D, Wang Z, Zhang M, Ma W, Jumaa H, Debatin K, Müschen M, Meyer LH, Davis RE, Burger JA. Pre-BCR Signaling in Precursor B Cell Acute Lymphoblastic Leukemia regulates PI3K/AKT, FOXO1, and MYC, and can be targeted by SYK inhibition. Leukemia. 2016 Jun;30(6):1246-54 (2016 IF 11.7)